Among the most noted changes in the immune system of the aged is the dramatic decline in T cell responses to pathogens. Influenza is a major cause of morbidity and mortality in the general population, but is a serious concern for the elderly, as influenza and its secondary complications represent the fourth leading cause of death in persons over the age of 65 in the United States. While age-related alterations in T cell responses are attributed to reduced thymopoiesis and increased homeostatic pressures to maintain lymphocyte numbers in the periphery, the dramatic decline in immunity may also reflect the presence of regulatory T cells (Tregs). Tregs not only prevent autoimmunity, but control a broad range of immune responses including the inhibition of transplant rejection, the prevention of the induction of anti-tumor responses, and the regulation of immune responses to infectious pathogens. Upon antigen stimulation Tregs, like conventional T cells, undergo expansion and as the response progresses, suppression by Tregs increases thereby maintaining the response in equilibrium. It is conceivable that with aging, wherein the chance for recurrent or chronic exposure to pathogens increases, this delicate balance may be upset by an accumulation of Tregs, which can potentially suppress responses to these pathogens. To this end, a significant increase in the number of Tregs in aged humans and aged mice has been observed. This increased frequency in Tregs with aging is somewhat paradoxical. It has been shown that Tregs develop from the thymus, and IL-2, although not essential for Treg development in the thymus, is critical for the maintenance of Tregs in the periphery and for the suppressive activity of Tregs. Yet, aging is associated with a marked reduction in both the export of thymocytes and the production of IL-2 by T cells. So how do Tregs increase in frequency with aging? Recently, it has been demonstrated that Tregs can be induced in the periphery from naove CD4 cells upon suboptimal stimulatory conditions. Furthermore, in normal naove mice, a fraction of Tregs has been shown to slowly proliferate without exogenous antigenic stimulation, presumably through the recognition of self-antigens in the periphery. Thus, it is conceivable that the accumulation of Tregs with aging may be the consequence of the generation of Tregs in the periphery and/or homeostatic expansion of Tregs that were generated earlier in life. We propose to elucidate the mechanism for the increased presence of Tregs in the aged and to determine the relative contribution by Tregs to the overall decline with aging in the immune response to influenza virus infection. PUBLIC HEALTH RELEVANCE: Findings from these studies will not only elucidate possible mechanism(s) for the increased number of Tregs but potentially elucidate methods to reduce their negative influence on influenza responses and possibly aid in improving the efficacy of current and future vaccines.